Are Hippocampal Hypoperfusion and ATP Depletion Prime Movers in the Genesis of Alzheimer’s Disease? A Review of Recent Pertinent Observations from Molecular Biology
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThis comprehensive review explores the hypothesis that hippocampal hypoperfusion and resultant ATP depletion are central, initiating events in the pathogenesis of Alzheimer’s disease (AD). The author synthesizes recent findings from molecular biology, genomics, metabolomics, and neuroimaging to support the argument that impaired blood flow and energy deficiency in the hippocampus trigger a cascade of cellular disturbances, ultimately leading to the hallmark features of AD.
The manuscript is logically structured, beginning with background information on AD and brain aging, then systematically addressing ATP metabolism, biosensors, high ATP-consuming processes, lipid metabolism, vascular anatomy, and genomic findings. Each section builds upon the previous, leading to a cohesive argument. The manuscript is of high quality and suitable for publication after minor revisions that are presented below:
- While the review is generally balanced, it could further address studies that do not support the hypoperfusion/ATP depletion hypothesis, or that emphasize amyloid and tau pathology as primary drivers.
- While the review touches on potential implications, it would benefit from a clearer discussion of how the hypoperfusion/ATP depletion model could influence clinical practice, including early diagnosis, risk stratification, and therapeutic development. Concrete examples or proposals for clinical trials or biomarker development would add value.
- Adding a graphical summary or schematic figure illustrating the proposed cascade from hypoperfusion to ATP depletion and subsequent neurodegeneration would greatly improve clarity and accessibility for readers, especially those less familiar with the molecular details.
Grammatical and typographical errors
Line 9 “Alzheimers dementia (AD) is a disease of aging brain.” Correct to “Alzheimer’s dementia (AD) is a disease of the aging brain.”
Line 31 “as brain ages” -> as the brain ages
Line 81 “ 20%”-> up to 20%
Line 85 “which are the major lipid constituents of membranes ; third it has an enormous area...” correct to “, which are the major lipid constituents of membranes . Third, it has an enormous area...”
Line 93-94 “in brain and incorporated into membranes.” Correct to “in the brain and incorporated into membranes .”
Line 111 “function” -> function
Line 159 “upto” -> up to
Author Response
- While the review is generally balanced, it could further address studies that do not support the hypoperfusion/ATP depletion hypothesis, or that emphasize amyloid and tau pathology as primary drivers.
- I have given more emphasis to amyloid and Tau where I could, without adding a lot of extra text in view of the length of the manuscript and the other additions requested. See: Introduction L48 & 85-88 (my copy showing corrections) with substituted refs 27 & 28 which strongly support amyloid; Discussion : L956-968 (I have tempered the interpretation of genomic study findings) & L1026-1027, & new section 8.1.1 (amyloid antibodies)
- While the review touches on potential implications, it would benefit from a clearer discussion of how the hypoperfusion/ATP depletion model could influence clinical practice, including early diagnosis, risk stratification, and therapeutic development. Concrete examples or proposals for clinical trials or biomarker development would add value.
- I have added a new Section (8.1) to the Discussion. Covers some of the proposed therapies which have undergone trial & are relevant to the proposal, & indicates the few with potential & some which failed. I have suggested compounds which could be included in the large marker trawls currently in progress
- Adding a graphical summary or schematic figure illustrating the proposed cascade from hypoperfusion to ATP depletion and subsequent neurodegeneration would greatly improve clarity and accessibility for readers, especially those less familiar with the molecular details.
There was a graphical abstract with the original submission. I have modified this a little to improve clarity at the request of Reviewer 2. I have drawn a new Figure (Fig. 9), placed at the beginning of the Discussion, which I hope makes things clearer
Grammatical and typographical errors
Line 9 “Alzheimers dementia (AD) is a disease of aging brain.” Correct to “Alzheimer’s dementia (AD) is a disease of the aging brain.”
'the' added
Line 31 “as brain ages” -> as the brain ages
'the' added
Line 81 “ 20%”-> up to 20%
changed
Line 85 “which are the major lipid constituents of membranes ; third it has an enormous area...” correct to “, which are the major lipid constituents of membranes . Third, it has an enormous area...”
Corrected
Line 93-94 “in brain and incorporated into membranes.” Correct to “in the brain and incorporated into membranes .”
Corrected
Line 111 “function” -> function
spelling corrected
Line 159 “upto” -> up to
corrected
Author Response File: 
Author Response.pdf
Reviewer 2 Report
Comments and Suggestions for AuthorsIn this study, the authors described the pathophysiological mechanism of Alzheimer's disease associated with ATP depletion in relation to various etiologies of the disease. The text is well organised in a logical and narrative manner, and the references to previous studies appear to be accurate. The authors proved their hypothesis through extensive research, including recent studies, and used high-quality figures to help readers understand.
The abbreviations in Table 1 are listed below the table. However, since the table is wide, it would be easier for readers if the abbreviations were included within the table instead of being listed separately.
Section 3, 'A role for ATP depletion in the genesis of AD', requires a schematic diagram.
The text in the figure is too small to read clearly. Increasing the font size would make it easier to read.
Author Response
The abbreviations in Table 1 are listed below the table. However, since the table is wide, it would be easier for readers if the abbreviations were included within the table instead of being listed separately.
I have done this and agree that it is easier to read
Section 3, 'A role for ATP depletion in the genesis of AD', requires a schematic diagram.
The text in the figure is too small to read clearly. Increasing the font size would make it easier to read
I considered these comments together since I think there are two issues
i) Section 3 covers the background chemistry of ATP depletion. I agree that a scheme would make it easier to follow, but I could not devise a figure which was not too cluttered, Instead, I have produced a simple Table (Table 2) which I hope will serve the purpose
ii) The other concerns the figure-did you mean the graphical abstract? I have modified this a little& increased the font size. I have also produced a more informative figure to go into the text (requested by another Reviewer) to make the proposed hypoxia cascade easier to follow. This is Fig.9 at the beginning of the Discussion. Increasing the font size in the text figures makes them cluttered with loss of clarity & I have not done this.
Author Response File: Author Response.pdf
Reviewer 3 Report
Comments and Suggestions for AuthorsThe author of this review summarized recent insights into possible risk factors and processes that contribute to the development of Alzheimer's disease, namely ATP depletion and brain hypoperfusion. The author describes in detail molecular mechanisms of brain aging and processes in the brain with very high ATP consumption, such as such the malate-aspartate shuttle, the glutamate/glutamine cycle, and axonal transport. This is excellent, very detailed and informative overview, which is supplemented by important tables, figures and schemas, addressed to the broad scientific and clinical community.
Major Comment:
In the brain, ATP is released during normal neuronal activity, but high levels of extracellular ATP occur at pathological brain states, such as seizures, hypoxia and also Alzheimer's disease (see Godoy et al. „Exploring the Role of P2X Receptors in Alzheimer's Disease“. Front. Pharmacol. 2019, 10, 1330, for example). The author should consider also mentioning extracellular ATP as a factor responsible for generation of Alzheimer's disease .
Minor Comments:
Line 50: “Table 4” is probably a mistake, this term does not belong here
Line 131: Abbreviation „OXPHOS“ is not explained when used for the first time
Line 193: „[Refer to Refs GH,2016,2018….“ Please correct
Line 232: instead of „Five“ should be five or 5
Line 467: „OAA“ ' is here by mistake
Line 496: [148Kaplan], please correct
Line 711: The term "AGPAT" is underlined, there's no reason.
Line 1016: „Hypertension in AD“ It is unclear if this is a new chapter
Line 1296: The abbreviation "ApoE"should be written uniformly throughout the manuscript
Author Response
Major Comment:
In the brain, ATP is released during normal neuronal activity, but high levels of extracellular ATP occur at pathological brain states, such as seizures, hypoxia and also Alzheimer's disease (see Godoy et al. „Exploring the Role of P2X Receptors in Alzheimer's Disease“. Front. Pharmacol. 2019, 10, 1330, for example). The author should consider also mentioning extracellular ATP as a factor responsible for generation of Alzheimer's disease .
Thank you for drawing my attention to this omission. I have added a brief summary to the end of Section 3.5, and also included the interaction with HIF-1 in Table 2
Minor Comments:
Line 50: “Table 4” is probably a mistake, this term does not belong here
Yes an error-I have removed
Line 131: Abbreviation „OXPHOS“ is not explained when used for the first time
I have expanded this
Line 193: „[Refer to Refs GH,2016,2018….“ Please correct
Corrected
Line 232: instead of „Five“ should be five or 5
changed to 'five'
Line 467: „OAA“ ' is here by mistake
OAA deleted
Line 496: [148Kaplan], please correct
Kaplan deleted
Line 711: The term "AGPAT" is underlined, there's no reason.
Underlining removed
Line 1016: „Hypertension in AD“ It is unclear if this is a new chapter
The subheading is unnecessary & has been removed
Line 1296: The abbreviation "ApoE"should be written uniformly throughout the manuscript
On checking, I found that APOE should be used for the gene & ApoE for the protein or peptide. I have made the appropriate changes throughout the text where necessary
Author Response File: Author Response.pdf
